This project is directed at understanding, characterizing, and evaluating the role of cytokines in the pathophysiology and treatment of infectious diseases. We have used mycobacterial diseases as the system in which to examine the role of cytokines and cellular interactions, especially those of the monocyte/macrophage, in the generation of an effective granulomatous response. We hope to determine the nature of the effective granulomatous response and thereby begin to dissect out conditions in which the granulomatous response is ineffective (e.g., tuberculosis) or inappropriate (e.g., sarcoid, Crohn's disease). We have characterized a family with ineffective granulomatous inflammation as demonstrated by disseminated Mycobacterium avium infection in the absence of HIV infection. These patients have low interferon gamma production due to interleukin-12 deficiency. The determination of interleukin-12 deficiency in an infectious disease confirms the role of interleukin-12 in the control of intracellular infections in humans. We have described other patients with low interferon gamma production not due to interleukin-12 deficiency, indicating that the interferon gamma generating pathway is complex. We have successfully treated these patients with subcutaneous interferon gamma. Interferon gamma is now being used in the treatment of multiple- drug resistant tuberculosis.